JP2021506963A - Use of Fluoroethyl Normemantine for Prevention and Treatment of Anxiety - Google Patents

Abstract

The present invention relates to one of fluoroethyl normemantine or salts thereof for treating anxiety, and more specifically post-traumatic stress conditions, alone or in combination with chemical antidepressant treatments or cognitive-behavioral techniques.

Description

The present invention relates to the discovery of the use of pharmaceutical ingredients in the treatment of disorders associated with anxiety and depression.

Numerous molecules have been developed to treat anxiety and anxiety associated with depression. However, these molecules have many drawbacks, especially significant side effects, which result in a relative increase in drowsiness, or even a schizophrenic psychotic state, or considerable treatment until a therapeutic effect appears. It is time consuming (days or even weeks) and carries the risk of anxiogenic effects during the treatment period.

Anxiety Human anxiety is a feeling of anxiety, instability, physical or mental illness, or a vague premonition of danger. Anxiety is further divided into two types: state anxiety and trait anxiety. State anxiety is "normal" anxiety associated with the particular situation in which the subject is placed. Characteristic anxiety is the "morbid" anxiety that is essential to the subject. It is permanent and independent of the particular situation.

Depression Depression is characterized by so-called depression episodes in which the patient experiences decreased mood, decreased vitality and decreased activity. Depression also has altered ability to experience joy, loss of interest, and rapid loss of concentration. In addition, significant fatigue is seen even after minimal effort, and sleep disorders are also seen. Patients frequently experience diminished self-esteem, feelings of guilt, and diminished self-esteem that can be so extreme that it develops into a desire for death and suicidal ideation. Depending on the number and severity of symptoms, the severity of depression is defined in three degrees: mild, moderate and severe.

Several mental disorders associated with anxiety and depression are listed in the International Classification of Diseases (ICD-10) advocated by the World Health Organization (WHO).

Phobic anxiety disorder: F40
Subjects exhibit anxiety symptoms that are induced exclusively or essentially by one or more specific harmless situations. As a result, patients either try to avoid such situations or endure with concern. This phobic anxiety is often associated with depression.

Mixed Anxiety Antidepressant Disorder: F41.2
In the case of this disorder, the subject presents with both anxiety and depressive symptoms, neither of which is clearly predominant and neither is severe enough to make a personalized diagnosis.

Obsessive-compulsive disorder (OCD): F42
This disorder is characterized by repetitive compulsive thinking or coercive behavior. Obsessive-compulsive thinking repeatedly invades the subject's consciousness in a fixed manner, even when the subject attempts to avoid them. Coercive behavior is also a repetitive, routine form of behavior that the subject does not feel direct joy in but cannot help but do. These purposes are to prevent the occurrence of objectively unlikely events, including misfortune for the subject. Subjects usually consider their actions absurd and repeatedly attempt to stop them. This disorder is almost always accompanied by anxiety and depression.

Post-traumatic stress disorder (PTSD): F43.1
Post-traumatic stress disorder develops after a subject has been exposed (directly or indirectly) to a traumatic event in a situation such as death, threat of death, serious injury, or sexual assault. This "traumatic" event, by definition, provokes a compulsive and intense fear response and represents an extremely stressful situation. Traumatic events result in a series of specific symptoms and behaviors. For example: flashbacks (repeated and intrusive memories of events, nightmares, etc.), avoidance behaviors (avoidance of memories, thoughts, people, situations, etc. that evoke traumatic events), cognitive and emotional changes (blame yourself) Tendency, persistent negative emotions, etc.), and finally overactivation of the nervous system (hyperawakening, sleep difficulties, etc.). People with this syndrome often develop severe depression or suicidal ideas (Shalev, Am. J. Psychiatry 155, 5, pp. 630-637, May 1998). This post-traumatic stress disorder phenomenon leads to a significant distortion of the encoding of event memory. Memory is preserved in a long-term, but biased manner, with amnesia in certain aspects and amnesia in other details that plague the subject.

Therefore, there is a real need for new solutions to effectively address anxiety disorders, whether or not they lead to depression.

Treatment of disorders with anxiety and depression:
Traditional treatments for anxiety, whether related to depression or not, include behavioral therapies, lifestyle changes and medications. However, many of the drugs used to treat these disorders are known to have annoying side effects or cause addiction or addiction (Thesis A. Dubois 2015 Universite de Bordeaux). Most of the therapeutic solutions currently used to treat anxiety-related disorders, and some of their side effects, can be found in the following review: Guidelines for the pharmacological treatment of anxiety disorders, obsessive. --compulsive disorder and posttraumatic stress disorder in primary care, B. Bandelow, International Journal of Psychiatry in Clinical Practice, 2012; 16: 77-84.

Among the earliest substances used were, for example, barbital derivatives known as barbiturates, which were widely used in the 1950s but at high risk of addiction or intolerance.

Later, other drugs for treating anxiety and depression, especially benzodiazepines such as diazepam (Valium®, etc.), were developed. These molecules were initially shown to be effective and relatively well tolerated, especially in France and the United States, and are still widely prescribed. Benzodiazepines usually have the ability to bind to cell receptors for GABA (γ-aminobutyric acid). This natural chemical compound is a major inhibitor of the central nervous system. By binding to cellular receptors, benzodiazepines increase the receptor's affinity for GABA, thereby increasing its strength by a factor of 10. However, these molecules have been shown to have significant substance dependence and other unwanted effects (such as cognitive impairment, schizophrenic disorders, drowsiness, withdrawal syndrome and recoil). Therefore, alternatives are being sought. In addition, benzodiazepines have not been found to be effective in treating OCD and other disorders associated with anxiety and depression.

Later, other classes of anxiolytic and antidepressant molecules were developed based on the action of other neurotransmitters: serotonin (5-hydroxytryptamine or 5-HT). Serotonin is a neurotransmitter released when information is exchanged between releasing and receiving neurons. Selective serotonin reuptake inhibitors or SSRIs include fluoxetine (Prozac®) and vortioxetine (Trintellix®, Brintellix®). Some information is lost between the transmitting and receiving neurons because the neurotransmitter is recaptured by the transmitting neuron and is not available to the receiving neuron. SSRIs act by blocking the recapture of serotonin by transmitting neurons, increasing the likelihood that serotonin will be recognized by receiving neurons, and thereby increasing the stimulation of those neurons. Many SSRI molecules have been developed to take advantage of this property (see, eg, patent EP0216555A2). The outcomes for anxiety and depression are very promising, but side effects have also been observed (especially disinhibition of behavior). In addition, evidence of the efficacy of SSRIs, especially paroxetine and sertraline, for reducing the severity of PTSD symptoms has been provided (P Carlier, Annales medico-psychologiques 166, 2008, 747-754). However, here too, side effects (paranoia, serotonin syndrome, etc.) and a certain number of intolerances or ineffectiveness have emerged, justifying the need for SSRIs in combination with other antidepressants (mood stabilizers, etc.). Be transformed.

Another neurotransmitter, glutamate, is also the subject of diligent research to develop new drugs. Glutamic acid has been previously recognized to activate multiple types of receptors (M. Teigell-Webb, EPHP paper): Glutamic acid is characterized by the name of their most selective agonist, Also named by it are three ion channel receptors: N-methyl-D-aspartic acid (NMDA), kainic acid (KA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropion. It acts on the acid (AMPA) receptor. Research on NMDA receptors is evolving more rapidly, as studies have shown that NMDA receptors are involved in interesting aspects of brain function. NMDA receptors are responsible for a wide variety of physiological roles: neural differentiation, synaptic connection formation during development, and synaptic plasticity in adults. In particular, NMDA receptors have been shown to be involved in learning and short-term memory in adults; in certain areas of the hippocampus, NMDA receptors enhance synaptic efficiency (or long-term potentiation), which acts as a medium for information storage. Helps to do. Finally, because NMDA receptors are involved in increased anxiety behavior after exposure to stress (RE Adamek et al., Physiology & Behavior, Vol. 65, Nos. 4/5, pp. 723-737, 1999). , Has become a major target for the development of PTSD treatments. It should be noted that the novelty of glutamate receptors, unlike other ligand-activated receptor channels, is that this receptor depends on both agonist (and co-agonist) binding and membrane potential. Competitive agonists and antagonists bind to the glutamate site. Non-competitive NMDA receptor antagonists are molecules that can bind to regulatory sites different from glutamate. For the treatment of anxiety, for example, NMDA receptor inhibitory peptides have been developed (Patent EP2175873).

In addition, so-called "channel blockers" are agents that bind to channels associated with the NMDA receptor when the NMDA receptor is in the "open" state (cells are depolarized and glutamate is bound). The most well-known "channel blockers" include ketamine, memantine and the like. Memantine has already shown a neuroprotective effect. For example, memantine has already been used in the treatment of Alzheimer's disease, but in patent US2010081723A1, for example, it has also been tested to treat behavioral disorders in children (autism).

In addition, non-competitive antagonists that bind to the phencyclidine (PCP) site of the NMDA receptor, such as ketamine, dizocilpine, and memantine, have also been tested for post-traumatic stress-related anxiety (Arthur L. Womble, AANA Journal). Please note that April 2013, Volume 81, No. 2.). For ketamine and dizocilpine, the positive results of these studies are strongly overshadowed by side effects (hallucinations, flashbacks, paranoia, etc.). It should be noted that ketamine strongly inhibits sensory filtering.

Nonetheless, several teams are exploring the development of ketamine, which gives a single injection of this molecule into rodents a week before fear conditioning, resulting in marked tetany during stabilization. An interesting preventive effect of reduction was shown (C. Denny et al., 1-13 in Neuropsychopharmacology (2017)). However, the effect is only visible at high doses in this model (30 mg / kg) and if the treatment is simultaneous with (or just before) conditioning, or if the protective treatment is too early (1 month ago). Cannot be reproduced.

US2014 / 057988A1 also proposes a method of using ketamine as an NMDA receptor antagonist for inhibition, alleviation or treatment of the development of mild anxiety. Mild anxiety is defined in the literature as an unpleasant feeling or concern. Although the literature discusses and cites methods of using memantine in the treatment of dementia, memantine has no anxiolytic effects and has schizophrenia-like adverse side effects.

WO2014 / 191424 describes how memantine derivatives, especially 2-fluoroethyl normemantine, are used in the treatment of neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.

Memantine has also been used to treat anxiety disorders, whether related to depression or not, such as PTSD and obsessive-compulsive disorder (G. Sani, Review Article CNS Drugs 2012; 26 (8)). : 663 ~ 690). In general, the action of memantine is positive when used in combination with other molecules (enhancement therapy). When used as a monotherapy, its efficacy is much weaker and controversial. For example, to treat OCD, memantine is used in combination with SSRIs such as fluoxetine or citalopram, or with other tricyclic antidepressants such as clomipramine. In general, the use of memantine as adjunctive therapy is well tolerated at low daily doses (less than about 15 mg / day). However, if the dose is too high, side effects such as discomfort, drowsiness and nausea have been observed. Although the results used in animal models of PTSD are not convincing, studies of several cases of human PTSD showed that memantine was used as an additional treatment to improve patient symptoms. In any case, memantine used alone cannot reduce or treat anxiety, whether mild or severe, whether associated with depression or not. Other combinations with other molecules include the combination of memantine with a synaptic vesicle glycoprotein SV2A inhibitor (US Pat. No. 2016030391A1) and the memantine / melatonin combination (Patent EP2905021A1).

In addition, memantine appears to have few side effects and is well tolerated, but appears to have unintended hypersedation (drowsiness, fatigue, dullness, etc.) and also results in increased dizziness at high doses (NR Swerdlow). , Neuropsychopharma., 2009, 34, 1854-1864), and Internet forums have reported recoil effects by patients. Furthermore, it is well known that memantine can induce schizophrenic side effects, especially at high doses, or has no anxiolytic effect.

Finally, in the case of NMDA receptors, the advantages and disadvantages of one antagonist are not necessarily the same as another, even if they are similar in structure, because the various antagonists do not act in one embodiment. It doesn't seem to be.

The latest class of molecules: catecholamine agonists have been proposed as a second-line treatment for PTSD (F. Ducrocq, L'Encephale, 2005; 31: 212-26). They have been used in pharmaceutical interventions to directly suppress noradrenalinergic hyperresponsiveness and have been tested in a small number of patients through open-label and double-blind trials. These agents include clonidine, guanfacine, prazosin and propranolol. Of these molecules, propranolol has been the subject of the most definitive study to date. It was thus argued that this non-selective β-adrenergic blocker could reduce the phenomenon of emotional memory consolidation immediately after a traumatic event as early as 1994 (Cahill L., Nature 1994; 371). : 702-4). A few years earlier, Famularo et al. Developed a study in children by establishing a three-stage BAB (off-on-off) design-based trial consisting of a four-week procedure that included a two-week washout period. This molecule is being tested for impaired disorders. In this study, eight of the 11 children who participated showed a marked improvement in PTSD symptoms (repetitive and autonomic nervous system hyperresponsiveness) during the treatment phase, but this improvement disappeared during drug holidays. (Famularo R, Am J Dis Child 1990; 142: 1244-7). This last factor significantly limits the importance of propranolol beyond the cognitive therapy contingencies of PTSD.

The lack of an efficient solution for PTSD treatment is also indicated by prescribing-related situations. Recent Studies (Tonix Pharmaceuticals Holding Corp. (TNXP) FORM 8-K | Current report Dec 8 2016. UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, DC 20549 Pursuant to Section 13 or 15 (d) of the Securities Exchange Act of 1934) In the United States, while only SSRI classes are FDA-approved for PTSD treatment, the major class of drugs prescribed is the benzodiazepine class in 55% of patients compared to 53% of SSRIs. Was shown to be.

EP0216555A2 EP2175873 US2010081723A1 US2014 / 057988A1 WO2014 / 191424 U.S. Patent 2016030391A1 EP2905021A1 WO2014191424A1 JP2007148435

Shalev, Am. J. Psychiatry 155,5, pp. 630-637, May 1998 Thesis A. Dubois 2015 Universite de Bordeaux Guidelines for the pharmacological treatment of anxiety disorders, obsessive --compulsive disorder and posttraumatic stress disorder in primary care, B. Bandelow, International Journal of Psychiatry in Clinical Practice, 2012; 16: 77-84 P Carlier, Annales medico-psychologiques 166, 2008, 747-754 M. Teigell-Webb, EPHP Treatise R.E. Adamek et al., Physiology & Behavior, Vol. 65, Nos. 4/5, pp. 723-737, 1999 Arthur L. Womble, AANA Journal April 2013, Volume 81, No. 2 C. Denny et al. Of Neuropsychopharmacology (2017), 1-13. G. Sani, Review Article CNS Drugs 2012; 26 (8): 663-690 NR Swerdlow, Neuropsychopharma., 2009, 34, 1854-1864 F. Ducrocq, L'Encephale, 2005; 31: 212-26 Cahill L., Nature 1994; 371: 702-4 Famularo R, Am J Dis Child 1990; 142: 1244-7 Tonix Pharmaceuticals Holding Corp. (TNXP) FORM 8-K | Current report Dec 8 2016. UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 Pursuant to Section 13 or 15 (d) of the Securities Exchange Act of 1934 http://psychobiologierouen.free.fr/?page_id=40, Course "Animal models of anxiety disorders" by M Roy L. Prut, European Journal of Pharmacology 463 (2003) 3-33 M Bourin, European Journal of Pharmacology 463 (2003) 55-65 F. Borsini, Psychopharmacology (1988) 94: 147-160 Kaouane N. Science 335, 1510 (2012) Zovkic, Neuropsychopharmacology REVIEWS (2013) 38, 77-93

Applicants faced the need for an efficient solution for PTSD treatment and therefore used molecules that are structurally derived from memantine but have very different dipole moments resulting from the introduction of fluorine atoms. Then, we envisioned a method of treating anxiety whether or not it was related to depression. In certain cases of PTSD, Applicants are surprisingly able to act as a defense, ie by administration at the same time as a traumatic event, and with both post-treatment or even delayed treatment. I found. Applicants further determined that the molecule did not exhibit many unwanted side effects of the prior art, or of the proposed treatment under study.

Therefore, the first object of the present invention is the formula (I) for use in the treatment or prevention of anxiety disorders in patients.

To propose a compound of the above or a pharmaceutically acceptable salt thereof.
Compound (I) for use according to the present invention is characterized by lacking a schizophrenia-inducing effect.

The term "lacking schizophrenia-inducing effect" is a dose of compound (I) for the treatment or prevention of anxiety disorders, including schizophrenia or schizophrenia delusions, paranoid delusions, hallucinations, attention deficit disorders. It means that it does not induce related symptoms such as withdrawal symptoms, delusional dispersal or disintegration symptoms.

In the second embodiment, the invention comprises a pharmaceutically acceptable salt of formula (II).

(In the formula, X ^- is chloride ion, bromide ion, iodide ion, acetate ion, methanesulfonic acid ion, benzenesulfonic acid ion, camphorsulfonic acid (camphosulfonate) ion, tartrate ion, dibenzoate ion, ascorbic acid ion, Indicates a counter anion selected from the group consisting of fumarate ion, citrate ion, phosphate ion, salicylate ion, oxalate ion, bromohydrate ion and tosylate ion)
The compound for use according to the first embodiment, which comprises the above.

Furthermore, a third object of the present invention is to propose a compound for use according to one of Embodiments 1 or 2, characterized in that anxiety disorders are associated with depression.
The compound is characterized by lacking a schizophrenia-inducing effect.

An object of a fourth embodiment of the present invention is to provide a compound for use according to one of embodiments 1 or 2, characterized in that the observed anxiety disorder is associated with insomnia. is there.

The present invention further describes, in a fifth embodiment, anxiety disorders with or without post-traumatic stress disorder (PTSD), specific phobia, social phobia, generalized anxiety disorder, agoraphobia and obsessive-compulsive disorder. The compound for use according to one of embodiments 1 to 4, characterized in that it is selected from the group consisting of sexual disorders.
The compound is characterized by lacking a schizophrenia-inducing effect.

In a sixth embodiment, the use according to one of embodiments 1-5, wherein the present invention is further used in a procedure for preventing the appearance of anxiety disorders associated with post-traumatic stress. Concerning compounds for.
The compound is characterized by lacking a schizophrenia-inducing effect.

Treatment of anxiety disorders associated with PTSD specifically involves treatment of at least one of the DSM5 criteria for PTSD selected from the group consisting of flashback, avoidance, negative cognition and mood, and hyperresponsiveness. Including.

Flashbacks specifically refer to related nightmares. Negative cognition and mood refer to depression.

According to embodiments of the invention, compound (I) or (II) is 1 mg to 1000 mg of compound (I) or (II), such as 5 to 250 mg, such as 5 to 100 mg, preferably 5 to 30 mg of compound (I). ) Or (II) can be administered at a dose containing. The dose may be administered, for example, 1 to 4 times daily, such as once, for example, twice, particularly three times, or even four times.

According to certain embodiments, compound (I) for use according to the invention is characterized by a lack of schizophrenia-inducing action. In a seventh embodiment, the invention relates to a compound for use according to embodiment 6, wherein the treatment comprises administering the compound at the same time as a traumatic event that causes post-traumatic stress.

Eighth embodiment of the invention further comprises the administration of the compound for 4-18 weeks after a traumatic event that causes post-traumatic stress, for the use according to embodiment 6. Regarding the compound of.

Compounds may be administered for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 weeks.

A ninth embodiment provides a compound for use according to one of embodiments 1-5, wherein the anxiety disorder is associated with post-traumatic stress, particularly established post-traumatic stress. ..
The compound is characterized by lacking a schizophrenia-inducing effect.

In a tenth embodiment, the present invention is for the use according to embodiment 9, wherein a patient presenting with anxiety disorder follows an antidepressant therapy selected from behavioral and pharmacological antidepressant treatments. Regarding the compound of.

Pharmacological antidepressant treatment means administration of at least one known chemical molecule for the treatment of depression. These include serotonin reuptake inhibitors such as fluoxetine, vortioxetine, fluoxetine, sertoralin, paroxetine, citalopram, escitalopram, duloxetine, milnacipran, venlafaxine, indalpine, dimeridine, dapoxetine.

In an eleventh embodiment, the present invention relates to a compound for use according to embodiment 10, wherein the patient is undergoing treatment based on propranolol.

According to a twelfth embodiment, the present invention relates to a compound for use according to one of embodiments 1-11, wherein the anxiety disorder is associated with an acute anxiety attack and an episode.

In the thirteenth embodiment of the present invention, the following components: formula (I)

A component containing the compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (A), a component containing propranolol and at least one pharmaceutically acceptable excipient (B). ), In particular for combination products for simultaneous, separate or sequential use.
According to certain embodiments of the product according to the invention, the product is characterized by a lack of schizophrenia-inducing action.

In the fourteenth embodiment of the present invention, the following components: formula (I)

A combination product containing a component (A) containing the compound of the compound or a pharmaceutically acceptable salt thereof, an antidepressant, particularly a component (C) containing one of the serotonin reuptake inhibitors according to the tenth embodiment. Provided is a product in which each of the components (A) and (C) is formulated with at least one pharmaceutically acceptable excipient.
According to certain embodiments of the product according to the invention, the product is characterized by a lack of schizophrenia-inducing action.

In a fifteenth embodiment, the invention relates to the product of embodiment 13, further comprising a ketamine-containing component (D) formulated with a pharmaceutically acceptable excipient.

In a sixteenth embodiment, the invention relates to the product of embodiment 14, further comprising a ketamine-containing component (D) formulated with a pharmaceutically acceptable excipient.

In a seventeenth embodiment, the invention further relates to a product according to embodiment 13, wherein ingredients (A) and (B) are adapted for simultaneous, separate or sequential administration.

In an eighteenth embodiment, the present invention relates to the product of embodiment 14, wherein the components (A) and (C) are adapted for simultaneous, separate or sequential administration.

In a nineteenth embodiment, the invention relates to the product according to embodiment 15, wherein the components (A), (B) and (D) are adapted for simultaneous, separate or sequential administration.

According to a twentieth embodiment, the present invention relates to the product according to embodiment 16, wherein the components (A), (C) and (D) are adapted for simultaneous, separate or sequential administration.

In a twenty-first embodiment, the present invention relates to a product according to one of embodiments 13-20, for use in the prevention or treatment of anxiety disorders in a patient.

According to a 22nd embodiment, the present invention relates to a product for use according to embodiment 21, wherein the patient is receiving cognitive behavioral therapy.

According to a 23rd embodiment, the present invention further relates to a product for use according to embodiment 22, characterized in that treatment of anxiety disorders follows cognitive behavioral therapy.

In a twenty-fourth embodiment, the present invention relates to the product according to embodiment 13 or 17, especially for use in the prevention or treatment of anxiety disorders in patients who have been repeatedly abused in childhood.

According to a twenty-fifth embodiment, the present invention provides the product for use according to embodiment 24, characterized in that the patient is receiving cognitive behavioral therapy.

According to the 26th embodiment, the present invention further comprises the use according to embodiment 25, wherein the components (A) and (B) are used separately in time and after cognitive behavioral therapy. Regarding products for.

FIG. 1 is a table showing the contents of the test of Example 5.

In fact, Applicants recently discovered a polarized derivative of memantine, 2-fluoroethyl normemantine (FENM) (see Formula I), with improved affinity for the NMDA receptor (Patent WO2014191424A1). ..

The numerator (I) is the formula (II)

(In the formula, X ^- is derived from a biological medium or is chloride ion, bromide ion, iodide ion, acetate ion, methanesulfonate ion, benzenesulfonate ion, camphor sulfonate ion, tartrate ion, dibenzoate. Protonized morphology and equilibrium state of ions, ascorbic acid ion, fumarate ion, citric acid ion, phosphate ion, salicylate ion, oxalate ion, hydrobromide ion and tosylate ion) It can be in. Therefore, the product of formula (II) is a pharmaceutically acceptable salt of the product of formula (I).

Note, for example, a particularly preferred acceptable pharmaceutical salt of fluoroethyl normemantine whose counter anion is the chloride ion, namely FENM-HCl.

In studies conducted during the development of NMDA as a biomarker, this molecule efficiently binds to the PCP (phencyclidine) site of the NMDA receptor when the NMDA receptor channel is in the "open" state. It has been shown to prevent excessive influx ^{of Ca 2+} , especially into cells. Interestingly, this increase in affinity is not due to strong binding to the NMDA receptor, but to the high specificity of the molecule to the region of the brain where the receptor is located and the long residence time in that region. .. In fact, the correlation that exists between NMDA and monoclonal antibodies, which indicate the efficiency of biolabeling, is lost when ketamine is injected. In addition, these preliminary studies showed rapid crossing of the blood-brain barrier.

Surprisingly, Applicants have shown that compound (I) (or a salt thereof, especially FENM-HCl) can be used to treat anxiety whether or not it is associated with depression. In certain cases of PTSD, surprisingly, Applicants are able to administer compound (I) or a pharmaceutically acceptable salt thereof defensively, i.e. at the same time as a traumatic event, and post-treatment. Or even found that it can work with both delayed treatments. Applicants further determined that this molecule did not exhibit many unwanted side effects of the proposed treatments in the prior art or under test.

Applicants also demonstrated the anxiolytic activity of product (I) described herein (light-dark box test and light gradient). In contrast, under the same conditions, memantine has been shown to have no anxiolytic activity.

The product (I) described herein has very significant anxiolytic activity, and its affinity with the NMDA receptor (measured by Ki) is on the same order as that of memantine.

In a light-dark box test based on the innate aversion of rodents to light, the increase in time spent in the lighting compartment was considered to reflect a decrease in anxiety level, and the decrease in anxiety level was the product of the present invention (I). Found on rodents treated with. Since no effect is found with memantine, it is concluded and confirmed that memantine has no anxiolytic effect.

Furthermore, we have also shown through sensory filtering tests that, unlike memantine, product (I) does not induce schizophrenia-inducing effects.

This, that is, treating anxiety whether or not it is associated with depression without inducing schizophrenia-inducing effects, is an important feature of product (I).

In the context of the present invention, the expression "co-administration with a traumatic event" means that compound (I) is administered within a time frame ranging from 48 hours before the traumatic event to 72 hours after the traumatic event. Means that. This "co-administration with a traumatic event" is also 48 hours before the traumatic event to 48 hours after the traumatic event, or 48 hours to 24 hours after the traumatic event, or 24 hours before the traumatic event. It can be up to 24 hours, or 24 hours to 48 hours before the traumatic event, or 24 hours to 72 hours after the traumatic event. In any case, co-administration over 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 weeks to achieve more efficient protection. It may be extended.

Therefore, the first object of the present invention is anxiety, whether or not it is associated with depression, especially by administering a compound of formula (I) or a pharmaceutically acceptable salt of formula (II). It is to provide a method for treating a patient suffering from a disorder. In particular, the method does not induce schizophrenia-inducing effects.

The present invention uses the compound of formula (I) or the pharmaceutically acceptable salt of formula (II) in the manufacture of a medicament for the treatment of anxiety disorders, whether related to depression or not. The purpose.

As described in the examples below, the anxiolytic and possibly antidepressant activity of compounds of formula (I) can be assessed by using the appropriate animal paradigm.

Therefore, according to the light-dark box experimental paradigm, Applicants have found that compounds of formula (I) or (II) according to the invention have significant anxiolytic properties, as opposed to memantine, which increases their time in the dark compartment. It was found that this property is obtained from the first injection at a dose of 10 mg / kg. By comparison, molecules such as fluoxetine have such anxiolytic activity at a dose of 5 mg / kg, but 7 days after treatment.

This finding was verified by conducting an open field test in the presence of a light gradient. Under this condition, the compounds according to the invention significantly limit, or even completely counteract, the avoidance of the brightest areas of the field by rodents during the exposure period, especially at doses of 10 mg / kg.

Similarly, through forced swimming tests, Applicants have found that compounds according to the invention significantly reduce rat immobility time as when treated with memantine or ketamine. This reflects the antidepressant effects of these molecules and compounds.

Applicants also further use the compounds according to the invention in fear conditioning tests, including elimination and stabilization phases, to their amazing advantage in the treatment of anxiety disorders, whether or not they are associated with depression. It was confirmed. This paradigm, commonly used to test the efficacy of PTSD treatment, is that the compounds according to the invention are conditioned in a surprising manner, especially at doses of 10 mg / kg and 20 mg / kg, more specifically. It is shown that when administered at the same time as the phase, the patient can be protected from persistent disability during the stabilization phase. No action was observed for propranolol in the same study. The effect observed for FENM is greater than the effect observed by C. Denny for ketamine injected in much higher doses one week before conditioning. Even more surprising, Applicants have similar beneficial effects in intensity, more specifically at the same dose, when the compounds according to the invention are administered before the stabilization phase, i.e. during the fixation of PTSD symptoms. Was found to be observable. No action was observed for propranolol in the same study.

Finally, the compounds according to the invention are also effective in eliminating persistence of injury, more specifically at doses of 20 mg / kg, especially when administered during the elimination phase. In this study, propranolol reduces tetany during the elimination phase, but this beneficial effect is lost during the stabilization phase.

It should also be noted that for memantine, a significant recoil effect is observed during the stabilization phase when administered during the elimination phase. This effect not only indicates that memantine and FENM have different mechanisms of action, but is consistent with clinically observed that memantine is not effective in treating PTSD.

Furthermore, Applicants observed that the compounds according to the present invention did not record an inhibitory effect on the plain pulse effect even when a beneficial effect was found, whereas memantine provided an inhibitory effect. As far as this schizophrenia-inducing effect is concerned, the absence of this schizophrenia-inducing effect is depressive, as most of the other proposed molecules (generally including benzodiazepines, especially diazepam and even ketamine) are observed. Highly preferred for the development of new treatments for anxiety, whether related to or not.

The compounds according to the invention can be administered in a variety of ways to obtain anxiolytic or antidepressant effects. The compounds according to the invention may be administered to a patient to be treated either orally or parenterally (subcutaneously or intravenously, etc.), alone or in the form of a pharmaceutical preparation.

The amount of compound administered may vary and may be any amount that provides anxiolytic and / or antidepressant effects. Depending on the patient and method of administration, the amount of compound administered can vary over a wide range from 0.01 mg / kg to 20 mg / kg, preferably 0.05 mg / kg to 15 mg / kg (patient weight) per dose.

The unit dose of the compound according to the present invention may include, for example, 5 mg to 1000 mg, preferably 5 to 30 mg, and may be administered, for example, 1 to 4 times a day.

The present invention relates to the use of medicinal products formulated from a compound according to the invention in connection with a method of pharmaceutically or cognitive behavioral therapy for treating anxiety disorders, whether related to depression or not.

For the purposes of the present invention, "cognitive-behavioral therapy" or CBT means cognitive-behavioral psychotherapy including a series of treatments for psychiatric disorders (particularly addiction, mental illness, depression and anxiety disorders). Share a reference approach for treatments to be based on knowledge derived from scientific psychology. CBT follows a relatively standardized protocol. CBT often assesses the progress of a patient being treated. CBT accepts an evidence-based medical approach. The peculiarity of CBT is the cognitive process by which CBT is considered to be the origin of emotional and patient disability, through hands-on training centered on behaviorally observable symptoms, and whether conscious or not. It is also about dealing with the patient's "now and here" difficulties through the attendance of a treatment specialist whose purpose is to intervene in known psychological processes. Due to the standardization of its practice, the effectiveness of CBT through reproducibility, which is one of the requirements of the scientific approach, has been recognized. CBT is specifically adapted for anxiety disorders (especially phobias) and addiction.

In particular, Applicants propose a combination of prophylactic administration of ketamine and administration of drugs containing compounds according to the invention after traumatic exposure to treat PTSD. Similarly, Applicants may administer propranolol in combination with cognitive therapy during the initial treatment period of PTSD and the present invention during the drug holiday to treat anxiety disorders presented by patients who have been abused, especially in childhood. It is proposed to use a combination of treatments with medicinal products containing the compound according to.

Animal model:
Development of drugs to treat the disease often uses animal models to test the efficacy and toxicity of the drug prior to testing in humans.

Animal models are considered valid if they meet the following three criteria: predictive validity, symptom similarity and constitutive validity. Of course, the results obtained from these animal models should not depend on the experimenter, and the use of automatic conditioning and observation means is being actively developed (photocells, use of video tracking, etc.).

Using Animal Models for Anxiety Animal models have been used for many years in the field of anxiety and have been improved as new observation techniques have been developed and as validation biases have been observed (eg, http). See the course "Animal models of anxiety disorders" by M Roy available online at //psychobiologierouen.free.fr/?page_id=40). Most animal models are developed using rodents.

In the case of anxiety, anxiety can be induced and measured by putting the animal in a dangerous situation by either simply exposing the animal model to a new environment or by exposing it to a pre-enhanced situation. It is possible. These animal models have been validated, in particular, by examining their properties that predict human responses.

Therefore, multiple animal models are commonly used to test anxiety conditions and have been validated by many studies:

--Open field study: This study consists of forcibly exposing an animal (rat or mouse) to a new environment and observing its behavior. Animals are usually placed in cages or boxes with grid floors that the animals are unaware of. Walking activity and behavior are then evaluated by recording the number of crossing grid lines, evacuation frequency, number of entries, and time spent in the central area. This animal model is considered a good model of "normal" anxiety when adapted to the new environment. This animal model has good predictability of human response to treatment (L. Prut, European Journal of Pharmacology 463 (2003) 3-33). In addition, the open field test is useful when it is performed for a long time (behavior recording time exceeds 2 hours) because it can monitor the motor activity and therefore the wakefulness of the animal, but the measurement in a short time is anxious. Brings information about.

--Light-dark box test: Another animal model of anxiety is based on a comparison of exploratory activity in light and dark compartments under the influence of anxiolytics and anxiolytics in open space (M Bourin, European Journal). of Pharmacology 463 (2003) 55-65). This paradigm is based on the innate aversion of rodents to bright areas and voluntary exploratory behavior in response to the stressful environment of rodents (new environment or light). The test device is divided into two compartments, one small, dark and safe compartment and the other large, bright and stressful compartment. This paradigm makes it possible to predict anxiolytic or anxiogenic drug-like activity in mice. The passage between each parcel is a signal of exploratory activity, and the length of stay in each parcel reflects disgust. Human-effective anxiolytics, classical drugs (benzodiazepines) and more recent anxiolytic compounds (drugs that act on serotonin agonists or neuropeptide receptors) are detectable in this animal model, which is simple and rapid. It has the advantage of being usable.

Open field test with light gradient: Appropriate combination of the above two models confirms the potential of the molecule as an anxiolytic by eliminating the "hidden" effect induced by the presence of dark compartments. Can be done.

Use of animal models for depression
--Forced swimming test:
This study has been used for many years in rats or mice to test the activity of antidepressants (F. Borsini, Psychopharmacology (1988) 94: 147-160) and animals in room temperature water. It consists of putting it in a filled water tank. After 15 minutes (pretest session), remove the animal from water and allow it to dry. After 24 hours, the animals are exposed to the previous conditions again and the total immobility time for 5 minutes is recorded (test session). An animal is immobile if it makes only the movements necessary to keep its head out of the water. This immobility is easier to evaluate in rats than in mice with less clear movement. Initially, the animal's greater immobility during the second inundation appeared to be an indicator that the animal learned that it could not escape during the pre-test. Therefore, this immobility appeared to be a definite sign of "despair" by animals. Although this interpretation is now more subtly different, as this increase in immobility can be explained by other reasons (such as responses adapted to situations already known), the study remains one of the major paradigms of depression. It is one and gives very good results for the antidepressant activity of the drug.

Use of Animal Models for PTSD By numerous research groups (eg, INSERM's Pier-Vincenzo Piazza and Aline Desmedt), PTSD-related dysfunction is not human-specific and is found in rodents. Is shown (see, for example, Kaouane N. Science 335, 1510 (2012)).

Therefore, animal models are commonly used to understand the pathogenic mechanism of PTSD (Zovkic, Neuropsychopharmacology REVIEWS (2013) 38, 77-93) or to test potential treatments for PTSD (eg, Patent JP2007148435). To.

Several animal models have been developed to mimic the traumatic events that induce the intense and repetitive phobic symptoms characteristic of PTSD.

Animal Pavlovian Fear Conditioning:
This animal model consists of Pavkic, Neuropsychopharmacology Reviews (2013) 38, 77-93): mice (or rats) exposed to danger (such as electric shock), specific cues. Or train to associate with the presence of an environment (eg, a sound signal). The memory of this association (danger-signal) is then tested by measuring the tetany behavior (due to fear) when the animal is re-exposed to the conditioning cues without actual risk.

Fear conditioning has many advantages as a model for PTSD. First, rodents, like patients with PTSD, are exposed to traumatic events, and the memory of these events is long-lasting. Second, re-experience of traumatic events or typical avoidance of PTSD puts rodents in a sonic signal or crisis without the need for actual re-exposure to the traumatic event itself (electric shock). It can be modeled by exposure to the relevant situation. In addition, the nervous system overactivity observed in patients with PTSD can be assessed by comparing the amplitude and occurrence of bursts that occur in response to traumatic sounds. Finally, studies of PTSD have shown that the brain regions involved include the amygdala, hippocampus and prefrontal cortex, which are also involved in animal fear conditioning.

Therefore, this animal model tests different treatments for the effects of different experimental variables or pathological fear memory by simply observing whether tetany behavior is increased, decreased, or suppressed. It is possible. Thus, the severity of traumatic events can be increased or decreased by reducing the intensity of the electric shock and attempting to relate it to the persistence and intensity of fear memory.

Other animal models are also commonly used as a PTSD paradigm for exposure to one or more predators with varying degrees of contact (odor, exposure to the animal itself, etc.).

Again, the development of PTSD symptoms is assessed after a period of time without exposure to crisis to simulate the long-term onset of PTSD pathology.

Fear elimination:
After the above fear conditioning, it may be important to apply a protocol to extinguish the fear. This period is typically provided 24 hours after conditioning.

To do this, conditioned animals are trained so that conditioning cues (sounds) no longer predict the occurrence of danger (electric shock).

Erasure may appear to counteract previous learning of fear, but is not equivalent to memory erasure or explicit forgetting, which, on the one hand, does not completely eliminate tetany during the erasure period, and on the other hand. This is because the response to the stimulus can reappear spontaneously or following shock. The elimination protocol models the re-learning of normal (fear-unmotivated) responses to cues (sounds) and is very useful in modeling PTSD.

Stabilization of fear:
It may be useful to add a stabilization period 24 hours after the elimination period to assess treatment performance. Typically, this period returns the animal to elimination conditions. This makes it possible to detect the recurrence (recoil effect) of tetany as well as the actual time difference of treatment.

In addition, "immobilized" PTSD, a situation in which an individual exposed (once or for a long period of time) to psychological trauma and treated (or not) in the conventional manner presents a residual disorder of this trauma. It becomes possible to model.

Using Animal Models for the Development of Schizophrenia Disorders Prepulse Suppression (PPI) Trials One of the major problems with treatments targeting the central nervous system remains a psychology that outweighs even the therapeutic benefits of treatments. Achieving the desired effect without the appearance of specific side effects. These effects are often prominent (rebound effect of benzodiazepines) or even paradoxical (anxiety-inducing effects of short-term serotonin reuptake inhibitors). In particular, these actions can induce destabilization of sensory filtering and cause symptoms similar to schizophrenia.

The plainpulse suppression test is based on the ability of the brain to adapt to moderate intensity stimuli and limit the effects of the same high intensity stimuli. In this test, animals were placed in a soundproof cage with 120 decibels (dB) sound pulses, or two pulses spaced about 100 ms apart, with the second pulse fixed at 120 dB intensity. It is used for one of two pulse sequences in which the intensity of the first pulse varies from 70 to 85 dB.

In normal animals, the first sound impulse acts to partially suppress the astonishment caused by the loudest sound. In animals with schizophrenic traits of psychiatric disorders, this suppression disappears more or less.

The rodent PPI study is a predominant study as long as it can be reproduced in humans where the adverse effects of schizophrenia disorders and pharmaceutical treatments (PCP, benzodiazepines, ketamine) can be detected.

In the examples below, the effects of memantine, propranolol and fluoroethyl normemantine (FENM, the subject of the present invention) are tested with untreated rats (Wistar) subjected to various tests related to depression or anxiety. And compare.

The test substance is intraperitoneally administered to rats in a volume of 5 ml / kg 30 minutes before the behavioral test is performed.

The solution to be injected is 95% (NaCl 0.9) of any of the molecules, in the form of hydrochloride (Memantin HCl and FENM-HCl), which is one of those salts for nitrogen derivatives, and itself for propranolol. % w / w aqueous solution) / 5% It was contained in the mixture of ethanol at the concentration shown below. In each experiment, refer to the dose per kilogram.

In this way, animals are administered a constant volume of solution equal to 5 ml / kg (with the closest weight difference) or 1.5 ml per 300 g of rat.

For each paradigm and each test solution, 12 rats are subjected to injection and behavioral testing. The control solution is saline.

(Example 1)
Anxiety treatment and gait activity Open field study:
"Normal" anxiety associated with the animal's gait activity and discovery of the unknown environment is measured 30 minutes after injection of the test solution using an open field video monitoring system for 2 hours. Recorded data read every 5 minutes includes time spent in the central area, vertical activity and number of dislocations.

Tables 1-3 below report the effects of FENM-HCl compared to memantine and control saline.

Results from various measurements indicate that FENM-HCl does not cause the drowsiness observed for memantine, even at high doses, and memantine reduces overall animal activity levels and field-centric presence time. Is shown not to improve. This effect is particularly pronounced over a 2-hour experimental period.

(Example 2)
Anxiety treatment (light and dark box paradigm)
In this example, a light-dark box test was used. Since this study is based on the innate aversion of rodents to light, an increase in staying time in the illuminated section is considered to reflect a decrease in anxiety levels.

The box used in this test is divided into a white compartment (600 lux) with high power lighting and a black compartment (about 5 lux) with a lid. The number of entries and the length of stay in the irradiation section (anxiety zone) are recorded for 10 minutes by a video monitoring system. In addition, the system is capable of distinguishing between 0-5 minute periods and 5-10 minute periods.

Table 4 shows the time of presence in the illuminated compartment for various doses of FENM-HCl compared to memantine and control saline.

The results showed that in animals treated with 10 mg / kg FENM solution, the time spent in the box illuminated compartment was significantly and significantly increased compared to controls (Student's t-test p <0.01), but an effect was observed with memantine. Indicates that it was not. This result shows that the compound according to the present invention has an anxiolytic effect, and that the mechanism of action and action are different from those of memantine.

This actually indicates that memantine has no anxiolytic effect.

(Example 3)
Treatment of anxiety (light gradient field paradigm)
In this example, the light-dark box test was modified by eliminating box compartmentalization and using a high intensity light gradient (600 lux). Since this study is based on the innate aversion of rodents to light, an increase in time spent in the area closest to the light source is considered to reflect a decrease in anxiety levels.

Animals are exposed to a sequence of 4 minutes in the dark (5 lux ambient light), 4 minutes in the presence of a light gradient, and again in the dark for 12 minutes divided into three quarters. Record the dislocations as in the open field test. Divide the observation field into four zones numbered 1 to 4 as the distance from the light source increases.

Table 5 below shows the effects of various doses of FENM-HCl compared to control solutions.

The results show that for animals treated with FENM-HCl, the avoidance of the most strongly illuminated areas by the animals is significantly reduced, representing an overall reduction in anxiety. At a dose of 10 mg / kg, the anxiety effect disappeared completely and the animals spent the same length of time in the presence and absence of light in the area close to the light source.

Moreover, it is found that the action of counteracting or reducing this anxiety has no other known action on the behavior of the animal, especially on the ability of the animal to move around.

(Example 4)
Treatment of depression (forced swimming)
In the forced swimming test, rats (12 per group) are forced to swim in a tank filled with water at 23 ° C (10 minutes on the first day and 6 minutes on the second day to acclimatize to environmental conditions).

Quantify rat behavior (stop swimming, reduce activity) with a video monitoring system.

The therapeutic solution to be tested is administered 30 minutes before the experiment on day 2. Animals that give up show (a) longer immobility times and (b) less time spent trying to energetically (desperately) escape from the beaker, ie, "depressive" behavior. It is an animal.

Table 6 below reports the effects observed with various doses of FENM-HCl on these two parameters compared to memantine and control saline.

The results show a very significant (p <0.001) reduction in immobility time and a marked increase in desperate action, indicating that memantine and compound (FENM) according to the invention have comparable antidepressant effects. This effect is observed at all dose levels and is particularly pronounced at 10 mg / kg.

(Example 5)
Treatment of PTSD (fear conditioning + erasure + stabilization)
An erasure protocol that models the re-learning of a normal (not fear-motivated) response to a signal (sound) is very useful in modeling PTSD.

Applicants used a fear conditioning test in which the signal (neutral conditioned stimulus) was the sound and the associated danger (disgusting non-conditioned stimulus) was the electric shock given from the floor of the box. This conditioning is followed by a fear-eliminating phase with injection of the treatment solution tested, followed by the test phase itself.

Fear Conditioning Period (FC): Fear conditioning is performed in a standard conditioning box (Situation A, white box in Table 7 (Figure 1)), with rats (8 per group) placed in the box for 180 seconds. Serve three "sound-electric shock" pairs for hours 381 seconds and 582 seconds later. Each sound lasts 20 seconds, and each electric shock lasts 1 second with a current of 1mA.

The Fear Elimination Phase (Ext.) Performs as follows: During a 25-minute session, the rats are placed in a box similar to that used in the final study (Situation B, Pink Box in Table 7 (Figure 1)). During this session, present the same sounds used during the conditioning session 24 times (20 seconds and 35 seconds each). Naturally, no electric shock is given, and the percentage of tetany (“freezing behavior”) time during this period is recorded.

Stabilization phase: In situation B, the day after the elimination phase, 30 minutes before the test phase, rats were injected with saline and subjected to three sonic sequences (the same sequence used for conditioning). Test the fear response and record the percentage of time that you remain stationary during this test period.

Table 8 below shows three treatment conditions:
-Protective action-one injection 30 minutes before the conditioning phase-early treatment-one injection 30 minutes before the elimination phase-late treatment-propranolol and one injection 30 minutes before the stabilization phase For various doses of FENM-HCl compared to control saline, we report the effect on the percentage of time the animal was immobile during the stabilization phase.

These results have the potential to virtually eliminate the tetany phenomenon during the stabilization phase (p <0.001), both at the time of conditioning and when administered during early or late post-traumatic treatment. Show that. Propranolol is not different from the control in the stabilization phase, but the elimination phenomenon is improved, which is consistent with the data published in the literature for rebound after drug withdrawal.

In addition, it should be noted that when memantine is administered at 10 mg / kg during the elimination phase, a significant recoil effect (increased tetany) is observed during the stabilization phase (+ 25% compared to the control).

(Example 6)
Lack of "sensory filtering" obstruction (PPI test).
The plainpulse suppression test is based on the ability of the brain to adapt to moderate intensity stimuli and limit the effects of the same high intensity stimuli. In this test, animals (12 per group) were placed in a soundproof cage with 120 decibels (dB) sound pulses, or two pulses spaced about 100 ms apart, with the second pulse being 120 dB. The intensity of the first pulse is fixed at the intensity of 70 to 85 dB and is used for any of the sequences of two pulses.

In normal animals, the first sound impulse acts to partially suppress the astonishment caused by the loudest sound. In animals with schizophrenic traits of psychiatric disorders, this suppression disappears more or less.

Table 9 below reports the observed effects on these two parameters in the presence of various doses of FENM-HCl compared to memantine or control saline.

These results show that 10 mg / kg of memantine induces a PPI inhibitory effect (p <0.01, equivalent to the effect reported in the literature for this compound), while FENM is at high doses (20 mg / kg). However, it does not induce the action. This means that memantine has the undesired effect of causing schizophrenia, while FENM has no undesired effect of causing schizophrenia.

In this study, the action of memantine and the implicit lack of action of FENM show schizophrenic side effects of memantine. This effect is particularly undesirable. In fact, this type of behavior is not desirable because it not only causes patient distress, but also causes anxiety-induced stress that increases rather than reduces anxiety.

Claims (18)

Formula (I) for use in the treatment or prevention of anxiety disorders in patients
Compound or pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt is formula (II).
(In the formula, X ^- is chloride ion, bromide ion, iodide ion, acetate ion, methanesulfonic acid ion, benzenesulfonic acid ion, camphorsulfonic acid ion, tartrate ion, dibenzoate ion, ascorbic acid ion, fumaric acid ion. , Citrate ion, phosphate ion, salicylate ion, oxalate ion, bromohydrate ion and tosylate ion)
The compound for use according to claim 1, which is characterized by the above. The compound for use according to any one of claims 1 or 2, wherein the anxiety disorder is associated with depression. The compound for use according to any one of claims 1 or 2, characterized in that the observed anxiety disorder is associated with insomnia. Anxiety disorders are characterized by being selected from the group consisting of post-traumatic stress disorder (PTSD), specific phobia, social phobia, generalized anxiety disorder, panic disorder with or without agoraphobia, and obsessive-compulsive disorder. The compound for use according to any one of claims 1 to 4. The compound for use according to any one of claims 1 to 5, characterized in that it is used in a procedure for preventing the appearance of anxiety disorders associated with post-traumatic stress. The compound for use according to any one of claims 1 to 5, wherein the anxiety disorder is associated with post-traumatic stress, particularly established post-traumatic stress. The compound for use according to any one of claims 1 to 7, wherein the anxiety disorder is associated with an acute anxiety attack and an episode. The following components: Equation (I)
Compound or a pharmaceutically acceptable salt thereof, and a component (A) containing at least one pharmaceutically acceptable excipient (A), a component containing propranolol and at least one pharmaceutically acceptable excipient ( Combination products, including B), especially for simultaneous, separate or sequential use. The following components: Equation (I)
A combination product containing a component (A) containing a compound or a pharmaceutically acceptable salt thereof, and a component (C) containing an antidepressant, each of which is at least one pharmacy. A combination product formulated with a qualifying excipient. The product of claim 9, further comprising a component (D) containing ketamine formulated with a pharmaceutically acceptable excipient. The product of claim 10, further comprising a component (D) containing ketamine formulated with a pharmaceutically acceptable excipient. The product of claim 9, wherein ingredients (A) and (B) are indicated for simultaneous, separate or sequential administration. The product according to claim 10, wherein the components (A) and (C) are indicated for simultaneous, separate or sequential administration. The product of claim 11, wherein the ingredients (A), (B) and (D) are indicated for simultaneous, separate or sequential administration. The product according to claim 12, wherein the components (A), (C) and (D) are indicated for simultaneous, separate or sequential administration. The product according to any one of claims 9 to 16, for use in the prevention or treatment of anxiety disorders in patients. The product according to claim 9 or 13, especially for use in the prevention or treatment of anxiety disorders in patients who have been repeatedly abused in childhood.